Project 443402

This proposal is focused on understanding how two members of the Eukaryotic Protein Kinase superfamily called Bud32 and Aurora A (AURKA) function to maintain the well-being of cells and organisms. Protein kinases typically modify other proteins by the addition of a tag called phosphate. This phosphate group regulates the modified protein so that it operates at the correct time and place in the cell. Bud32 is one of the most ancient members of the Eukaryotic Protein Kinase superfamily. It is present in a large complex called KEOPS that modifies tRNA molecules. tRNA molecules are important because they allow for the conversion of the information in our genes into functional products called proteins. How exactly Bud32 regulates KEOPS function is a long-standing mystery. Here we propose a series of experiments to address this question. The resultant work has important implications for human disease as the breakdown of KEOPS function gives rise to Galloway-Mowat syndrome, a severe developmental disorder that manifests in microcephaly and renal disease and results in childhood death. AURKA plays multiple roles in how cells replicate themselves. Each of the different roles involves the participation of partner proteins. Here we are studying the partner protein called Bora, which works together with AURKA to regulate when exactly a cell commits to undergoing one round of cell division. As described in a recently publish manuscript, we have discovered many of the details of how Bora and AURKA work together. In this proposal, we seek to answer the remaining questions of how exactly Bora binds and turns on AURKA. This work has important implications for the design of better drugs that bind and inhibit AURKA to treat cancer.